(Z)-2-(1H-indol-3-yl)-3-(isoquinolin-5-yl)acrylamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: (Z)-2-(1H-indol-3-yl)-3-(isoquinolin-5-yl)acrylamide
• 英文别名: (Z)-2-(1H-indol-3-yl)-3-isoquinolin-5-ylprop-2-enamide
• 化学式: C₂₀H₁₅N₃O
• 分子量: 313.359
• InChiKey: ZHVVODQPDSRPGJ-YVLHZVERSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  71.8
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  吲哚-3-乙腈 在 sodium methylate 、 potassium hydroxide 作用下， 以 甲醇 、 叔丁醇 为溶剂， 反应 18.39h， 生成 (Z)-2-(1H-indol-3-yl)-3-(isoquinolin-5-yl)acrylamide 、 (E)-2-(1H-indol-3-yl)-3-(isoquinolin-5-yl)acrylamide
  参考文献：
  名称：

  Discovery of the cancer cell selective dual acting anti-cancer agent (Z)-2-(1H-indol-3-yl)-3-(isoquinolin-5-yl)acrylonitrile (A131)

  摘要：

  Selective targeting of cancer cells over normal cells is a key objective of targeted therapy. However few approaches achieve true mechanistic selectivity resulting in debilitating side effects and dose limitation. In this work we describe the discovery of A131 (4a), a new agent with an unprecedented dual mechanism of action targeting both mitosis and autophagy. Compound 4a was first identified in a phenotypic screen in which HeLa cells treated with 4a manifested mitotic arrest along with formation of multiple vesicles. Further investigations showed that 4a causes an increase in mitotic marker pH3 and autophagy marker LC3. Importantly 4a induces cell death in cancer cells while sparing normal cells which regrow after 4a is removed. Dual activities against pH3 and LC3 markers are required for cancer cell selectivity. An extensive SAR investigation confirmed 4a as the optimal dual inhibitor with potency against a panel of 30 cancer cell lines (average antiproliferative GI(50) 1.5 mu M). In a mouse model of paclitaxel-resistant colon cancer, 4a showed 74% tumor growth inhibition when administered at a dose of 20 mg/kg IP twice a day. (C) 2018 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.07.011